Browsing by Author "Serafim, S."
Now showing 1 - 9 of 9
Results Per Page
Sort Options
- 47,XY,+del(X)(q21.31)/46,XY mosaicism in prenatal diagnosis - case report of a rare eventPublication . Ferreira, C.; Tarelho, A.; Marques, B.; Serafim, S.; Pedro, S.; Ferreira, A.; Correia, H.OBJECTIVES: Aneuploidies involving the sex chromosomes are the most common anomalies in humans. In many cases these anomalies are present in mosaic and may involve either the whole chromosome or just part of it. These anomalies constitute a challenge in prenatal diagnosis because it is generally very difficult to establish a reliable genotype-phenotype correlation. Here we report a rare event of a mosaic in which one cell line carries an additional abnormal X chromosome, with a terminal deletion at q21.31 region, and a normal XY constitution in the majority of the cells. METHODS: A healthy 36-year-old G1P1 woman was referred for prenatal diagnosis at 11+5 weeks of gestation for increased nuchal translucency. Chorionic villus biopsy was performed and molecular rapid aneuploidy result indicated an anomalous situation for the X chromosome in a male fetus. As the material was not sufficient to establish a culture an amniocentesis was performed at 17+3 weeks and karyotyping and microarray were performed in order to characterize the anomalous result. RESULTS: The results obtained indicated the presence of a mosaic involving an extra X chromosome with a terminal deletion, [47,XY,+del(Xq)/46,XY.arr[GRCh37] Xp22.33q21.31(169921_89283237)x1~2], which is compatible with a Klinefelter syndrome variant. CONCLUSIONS: Pregnancies affected by X chromosome aneuploidies diagnosed prenatally are at an increased risk of adverse fetal and neonatal outcomes. High quality information is critical for informed decision-making in pregnancy following a prenatal diagnosis of sex chromosome aneuploidy. The participant shall be able to understand the importance of breakpoints definition and the impact that a mosaicism situation have in prenatal diagnosis.
- Chromosomal disorders and male infertilityPublication . Simão, L.; Caetano, I.; Pedro, S.; Silva, M.; Ambrósio, P.; Gonçalves, J.; Brito, F.; Marques, B.; Alves, C.; Serafim, S.; Geraldes, M.C.; Correia, H.Male factor infertility is considered a complex disorder with a largely unknown etiology that affects about 7% of men. In general, genetic abnormalities account for 15%-30% of condition and Y chromosome microdeletions are also frequent. The study, based on our casuistic, aimed at contributing to a better understanding of the genetic causes of infertility. A group of 410 idiopathic infertile men with non-obstructive azoospermia, oligozoospermia, or unknown semen quality (based on clinical evaluation and/or sperm counts) was retrospectively selected. Conventional karyotype was performed in all samples; Y microdeletion screen was performed in 247 samples. Forty two abnormal karyotypes (10.2%) were found, indicating an elevated frequency of chromosome abnormalities among the selected infertile men, as compared to that of newborn populations (≈0.4%). This frequency is higher than that reported in most similar studies that pointed to frequencies ranging from 2.2%-14.3%. Klinefelter´s syndrome was the most common chromosome disorder (4.9%). There were 18 cases with 47,XXY karyotype and 2 cases of mosaicism involving lines 47,XXY and 46,XY. Reciprocal translocations were identified in 10 cases (2.4%), particularly in men with unknown semen quality. Overall, reciprocal translocations have been found in approximately 1% of the infertile men and more commonly in azoospermics than in oligozoospermics. However, this type of association was not found in the present study. On the other hand, Y microdeletions were identified in 16/247 cases (6.5%), more frequently in azoospermics (13.3%, corresponding to 8/60 azoospermics). Among these 8 cases, 7 presented deletions at the AZFc region. The marked presence of chromosomal abnormalities and Y microdeletions enphasizes the relevance of studying both factors in infertile men to improve genetic counseling, to allow the development of appropriate therapies, and to expand the knowledge about the ethiology of male infertility.
- Classification of the dup 15q13.3 CNV: A National data collectionPublication . Sousa, A.; Serafim, S.; Santos, R.; Custódio, S.; Ávila, M.; Dupont, J.; Dias P, P.; Moldovan, O.; Melo, J.; Ferreira, S.; Pires, L.; Leão, M.; Sá, S.; Prior, C.; Alves, C.; Barreta, A.; Tarelho, A.; Marques, B.; Pedro, S.; Lopes, F.; Maciel, P.; Correia, H.; Dória, S.; Rendeiro, P.; Castedo, S.; Carreira, I.; Sousa, A.B.Introduction: The proximal region 15q11q14 is one of the most unstable regions in the human genome, with six recognizable break points (BP1-BP6). In 15q13.3 there is a recurrent small CNV (BP4-BP5) consisting of a 350-680 Kb duplication, encompassing the CHRNA7 gene, which encodes the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor. Although microdeletions of CHRNA7 are known to cause intellectual disability and neuropsychiatric phenotypes with high penetrance, the patogenicity of CHRNA7 duplications remains unclear. Microduplication 15q13.3 seems to be associated with a phenotypic spectrum of cognitive impairment and neuropsychiatric/neurobehavioral disorders. However, the penetrance of this CNV is considered incomplete since it is present in clinically unaffected individuals in the general population and it is frequently inherited from apparently clinically normal parents. Nonetheless, some pedigree studies have found a history of neuropsychiatric problems among carrier family members. This study aimed at re-evaluating the dup 15q13.3 CNV in national laboratories. Materials and Methods: Our study collected data on 15q13.3 microduplications in eight Portuguese genetics laboratories, among subjects referred for microarray. Results: Here we present a total of seventeen cases with dup 15q13.3. The subjects had somewhat variable phenotypes, with a bias towards developmental delay and autism spectrum disorders. Inheritance was established for eight of the subjects, and the majority originated from the father. We had no access to clinical data on carrier parents. No de novo CNV was found. All laboratories involved classified this variant as of uncertain significance. Discussion/Conclusion: To better determine whether this CNV is benign or pathogenic, careful characterization of patient and control cohorts must be performed, including detailed patient phenotyping, inheritance, clinical evaluation of carrier parents, prevalence in controls, as well as genetic functional studies. We strongly support the creation of a national database for uncertain CNVs in order to clarify the relevance of these recurrent findings, allowing a definitive classification in either pathogenic or benign.
- Derivative chromosome 7 in a newborn with hypotelorism, cleft palate, agenesis of corpus callosum and semilobar holoprosencephalyPublication . Simão, L.; Serafim, S.; Brito, F.; Ventura, C.; Scortenschi, E.; Santos, V.; Correia, H.Cytogenetically visible unbalanced chromosome rearrangements involving the euchromatic regions most often result in severe phenotypic features. Often, it is not possible at microscopic level to distinguish if a chromosomal anomaly involves one or more than one chromosome. In these cases, the parents study is fundamental and is usually the first line of study. We report a female newborn with multiple anomalies. Ultrasonography at 32+6 weeks of gestation revealed moderate ventricular dilatation, microcephaly and intrauterine growth restriction (IUGR). Delivery was at 35 weeks and microcephaly, hypotelorism, complete medium cleft palate with nasal depression, agenesis of the corpus callosum, thalamic fusion and fusion of the lateral ventricles in the frontal region suggestive of semilobar holoprosencephaly (HPE) was observed. Seizures and nistagmus were described since the eighth day. Hypotonia was present. In addition, diabetes insipidus was diagnosed. Sepsis was developed at day 14 followed by death at day 18 in consequence of seizures and respiratory insuficiency. Cytogenetic analysis revealed an abnormal chromosome 7qter as a result of an unbalanced segregation of a maternal reciprocal translocation t(7;19), with breakpoints at 7q36.1 and 19q13.42. The newborn karyotype is 46,XX,der(7)t(7;19)(q36.1;q13.42)mat. The patient presented a partial trisomy of the region 19q13.42→qter and a partial monosomy of the region 7q36.1→7qter. Partial monosomy of chromosome 7qter has been characterized by a wide phenotypic manifestations, but HPE, microcephaly, midface hypoplasia, maxillary anomalies and sacral agenesis are frequently described. However, is not often reported in newborns. Partial trisomy 19q is a rare and severe condition, and has been described associated with low birth weight, growth retardation, microcephaly, seizures, dysmorphic facial features, short neck, clynodactyly, heart malformations, anomalies of the genitor-urinary and gastrointestinal tract. To our knowledge, there is only one previous case of der(7)t(7q;19q)(q36.1;q13.43) described, in a fetus who presented severe sacral agenesis and IUGR. The case herein reported presents some of the most common features of 7q36 partial monosomy and 19q terminal trisomy, although some of them are present in both conditions. The presence of those two imbalances may complicate the final phenotype but the important matter will be the counseling of the couple and to prevent future imbalances in their offspring.
- Diagnóstico pré-natal tardio de uma gestação com anomalias ecográficas e com duplicação da região 7q11.23Publication . Simão, L.; Serafim, S.; Ferreira, C.; Alves, C.; Brito, F.; Silva, M.; Furtado, J.; Viegas, M.; Pedro, S.; Marques, B.; Rodrigues, M.; Sá, J.; Castro, M.J.; Mendes, P.; Vassal, H.; Correia, H.Introdução: O diagnóstico pré-natal (DPN) atempado de anomalias cromossómicas em fetos com anomalias ecográficas é fundamental no prognóstico da gravidez, ou na sua possível interrupção. Assim, a realização das ecografias fetais nas semanas preconizadas é determinante para a gestão dos casos anormais. Descrevemos um caso de uma gravidez mal vigiada, com ecografia fetal realizada às 29 semanas de gestação, onde se identificou uma dilatação pielo-calicial grave no rim esquerdo e dúvida na área cardíaca. Objectivos: Evidenciar que a vigilância atempada das gestações conjuntamente com a análise por microarray aumenta a capacidade de diagnóstico em gestações com anomalias fetais detetadas ecograficamente.
- Mudanças no diagnóstico pré-natal cromossómico: indicações clínicas, amostras biológicas, metodologias e cromossomopatiasPublication . Simão, L.; Silva, M.; Alves, C.; Brito, F.; Serafim, S.; Ambrósio, P.; Geraldes, M.C.; Marques, B.; Ferreira, C.; Pedro, S.; Furtado, J.; Ventura, C.; Tristão, J.; Ferreira, A.; Correia, J.; Correia, H.Introdução: As mudanças no diagnóstico pré-natal de anomalias cromossómicas (DPN) nos últimos 10-15 anos foram contínuas e significativas. Objetivos: Propômo-nos analisar essa evolução: mudanças nas indicações clínicas; introdução das biópsias de vilosidades coriónicas (BVC); utilização do diagnóstico rápido de aneuploidias (DRA); estudos por microarray; alterações cromossómicas encontradas. Metodologia: Fez-se a avaliação retrospetiva nas gestações com amostras estudadas nos triénios 2004-2006 e 2014-2016. Analisaram-se os parâmetros indicação clínica, tipo de amostra, metodologias utilizadas e resultados. Resultados: Identificaram-se 68 fetos com cariotipo anormal em 2210 cariotipos (3,1%) em 2004-2006 e 208 fetos com cariotipo anormal em 2315 cariotipos (9,0%) em 2014-2016. A maior frequência de anomalias encontrou-se nos casos de rastreios ecográficos e combinados indicativos de risco acrescido de anomalia numérica e de progenitores portadores de alterações cromossómicas. As BVC permitiram respostas precoces nas gestações com anomalias numéricas e, adicionalmente, um aumento desses cariotipos (7.5% das amostras). O DRA permitiu ter uma resposta rápida nas anomalias numéricas mais frequentes (2 dias). As anomalias estruturais foram menos preponderantes nos cariotipos anormais (32,4% em 2004-2006 e 14.4% em 2014-2016). Discussão e conclusões: O DRA reduziu o tempo de resposta e das decisões sobre o futuro das gestações. O microarray permitiu identificar alterações sindromáticas em situações não resolúveis por outras metodologias. A utilização de BVC permite estabelecer uma melhor correlação fenotipo-genotipo em menores idades gestacionais. No entanto, as gestações com anomalias numéricas têm algum risco de perda fetal no primeiro e início do segundo trimestres. Assim, algumas BVC com cariotipos anormais resultariam em perdas espontâneas, o que poderia disponibilizar outros casos para DPN. Por outro lado, o menor número de anomalias estruturais equilibradas encontrado pode reduzir o conhecimento da variação genética nas famílias e na população. Um novo paradigma resulta da implementação dos testes não invasivos no DPN, para os quais ainda não conhecemos todas as limitações e repercussões.
- Multiple non contiguous copy gains and a terminal loss in 8q24 identified in a fetus with cleft palate and lipPublication . Serafim, S.; Pedro, S.; Marques, B.; Tarelho, A.R.; Ferreira, C.; Simao, L.; Viegas, M.; Silva, M.; Alves, C.; Mourinha, V.; Ferreira, A.; Correia, H.Objectives: Chromosomal microarray analysis (CMA) is the recommended genetic test in pregnancies with ultrasound abnormalities but in some cases karyotype may still be needed to clarify the underlying mechanism of complex rearrangements. Here we report the case of a fetus from a healthy 24-year-old G1P0 woman, with a low risk for common aneuploidies in the 1st trimester prenatal screening but referred for CMA at 17+6 weeks of gestation due to cleft palate and lip in the 1st trimester ultrasound. Method: After a normal result in the rapid aneuploidy diagnostic test we performed CMA using ThermoFisher Cytoscan™ 750K. Our reporting resolution includes gains and losses larger than 35 Kb, considered clinically relevant for the course of the pregnancy. In this case further tests were done to assess recurrence risk and a possible chromosomal rearrangement: CMA and karyotype on the parents and karyotype on the fetus. Results: The CMA profile revealed a female fetus with three non-contiguous interstitial copy gains and a terminal loss in the long arm of chromosome 8 (8q24), as follows: - x4 copy gain at 8q24.12q24.13 with 585 Kb - x2 copy neutral region with 1.5 Mb - x4 copy gain at 8q24.13 with 2.9 Mb - x2 copy neutral region with 1.2 Mb - x3 copy gain at 8q24.21q24.23 with 17.8 Mb - x1 terminal loss at 8q24.3 with 130 Kb The fetal karyotype showed, in one of the chromosomes 8, an abnormal pattern in the long arm with a larger relative size. After parental studies the reported copy number variants were shown to be de novo. Conclusions. Most of the cases reported in the literature with gains along 8q result from a rearrangement involving another chromosome making it challenging to assess a genotype-phenotype correlation (PMID: 34265769; PMID: 31141803; PMID: 34794751). The few cases of individuals reported with isolated gains in the 8q24 have been described as having different features, depending on the size of the gain, and those may include facial dysmorphysms, clef lip and palate, developmental delay, among others (PMID: 25506438; PMID: 11484205; PMID: 33316910; UNIQUE - rarechromo.org: duplications of 8q). Recently a fetus with multiple congenital abnormalities, including clef palate, was reported having a similar imbalance, and although the parents decided to keep the pregnancy the baby died soon after birth given the extension of the congenital abnormalities (PMID: 30638476). The CMA results in our case explained the clef palate and lip identified in the fetus and, after genetic counseling, the parents opted to terminate the pregnancy. Although the identified non-contiguous gains and the terminal loss may suggest a mechanism of chromothripsis/chromoanagenesis for the arising of this abnormal chromosome 8, no further studies were performed after determining that the parents had a normal result and therefore a low recurrence risk for future pregnancies.
- Prenatal diagnosis of 7q11.23 duplication in a fetus with renal pelvic dilatation and the postnatal outcomePublication . Serafim, S.; Ferreira, C.; Simão, L.; Alves, C.; Brito, F.; Silva, M.; Furtado, J.; Viegas, M.; Pedro, S.; Marques, B.; Rodrigues, M.; Sá, J.; Castro, M.J.; Mendes, P.; Vassal, H.; Correia, H.7q11.23 duplication syndrome is a multisystemic developmental disorder characterized by variable manifestations, such as speech delay, mild craniofacial anomalies with distinctive facial features, and intellectual ability ranging from mental retardation to normal cognitive development. Approximately 30% of individuals with 7q11.23 duplication have one or more congenital anomalies. Penetrance is complete with variable expression of phenotypic features. Prevalence has been estimated at 1:7,500-1:20,000. The 7q11.23 duplication is frequently inherited from a parent. Here we report a 33-year-old woman referred for prenatal diagnosis at 29 weeks of gestation due to fetal renal pelvic dilatation. Chromosomal microarray analysis (CMA) was performed after a normal molecular rapid aneuploidy test result and identified a 1.44 Mb duplication at 7q11.23 - arr [GRCh37] 7q11.23 (72,700,467-74,136,633)x3 - overlapping the 7q11.23 duplication syndrome region, in a female fetus. The gain was inherited from the mother which had no previous clinical evaluation but a later reassessment revealed mild cognitive delay and language impairment. Delivery was at 35 weeks due to a maternal respiratory infection with acute pulmonary edema. Newborn resuscitation was required for neonatal respiratory depression with an Apgar score of 1'-2, 5'-4, 10 '-8. Birth weight and length was 2140g and 43cm respectively, with a head circumference of 32cm. In the neonatal period a transient systolic murmur was identified with no alterations on the echocardiogram. Renal and bladder ultrasound showed pelvic dilatation with no changes of the ureteral tract, suggesting a relation with ureteropelvic junction syndrome. Left pyeloplasty for the ureteropelvic junction syndrome was performed at 14 months of age. Clinical evaluation at the age of 22 months revealed psychomotor development delay with delayed speech, facial features overlapping Williams-Beuren syndrome, and the systolic murmur grade I/VI was still present. Growth and weight were both normal. To the best of our knowledge this is the second prenatal case of 7q11.23 duplication described. Although genitourinary tract abnormalities are not the most common feature in patients with 7q11.23 duplication, congenital anomalies of the urinary tract can occur in 15%-18%, including hydronephrosis and unilateral renal agenesis. This shows that the ultrasound abnormalities not always suggest a specific syndrome but after the identification of a pathogenic CNV made possible by the use of CMA a correlation may be achievable. Additionally the discovery of CNVs in prenatal CMA may go beyond the context of the current pregnancy allowing for the identification of carriers thus having a larger impact in a family's health management and genetic counseling.
- Prenatal diagnosis of mosaic ring chromosome 16 - a rare event with uncertain prognosisPublication . Brito, F.; M. Silv, M.; Alves, C.; Ferreira, C.; Serafim, S.; Simão, L.; Marques, B.; Pedro, S.; Tarelho, A.; Furtado, J.; Lopes, P.; Silva, N.; Viegas, M.; Fernandes, A.; Teixeira, F.; Gomes, S.; Correia, H.Ring chromosomes are rare cytogenetic findings (prenatal frequency ~ 0.0075%) often associated with an abnormal phenotype, depending of the chromosomal origin, genetic content and the presence of a mosaic. Supernumerary ring chromosome 16 [r(16)] is rarely observed and mosaicism makes the genotype/phenotype correlation difficult. We report a de novo mosaic r(16) detected after prenatal diagnosis in a woman referred for advanced maternal age. Multiplex ligation-dependent probe amplification (MLPA) for aneuploidy testing of chromosomes 13, 18, 21 and X was normal. Karyotype was 47,XX,+r[10]/46,XX[15]. Chromosomal microarray analysis (CMA) on DNA obtained from long-term cultured amniocytes did not detect any alterations. MLPA with a pericentromeric probe kit on an uncultured sample showed a chromosome 16 gain, encompassing 16p11.2 and 16q11.2 regions, including TGFB1I1, AHSP, VPS35 and ORC6 genes, leading to partial characterization of the r(16). Although no phenotype has been correlated with overexpression of these genes, the 16p11.2 region is associated with neurodevelopmental disorders. Nevertheless individuals with microduplication of 16p11.2 and normal development have been described. The lack of a precise definition of genetic content of the r(16) and its mosaic form leads to uncertain prognosis of clinical outcome.